iles to amides by a chitin-supported ruthenium catalyst †

Chitin-supported ruthenium (Ru/chitin) promotes the hydration of nitriles to carboxamides under aqueous conditions. The nitrile hydration can be performed on a gram-scale and is compatible with the presence of various functional groups including olefins, aldehydes, carboxylic esters and nitro and benzyloxycarbonyl groups. The Ru/chitin catalyst is easily prepared from commercially available chitin, ruthenium(III) chloride and sodium borohydride. Analysis of Ru/chitin by high-resolution transmission electron microscopy indicates the presence of ruthenium nanoparticles on the chitin support.


Introduction
The catalytic hydration of nitriles (RCN) to carboxamides (RCONH 2 ) represents a fundamentally important pathway to these products in both laboratory and industrial contexts. [1][2][3] Since the discovery of alumina-supported ruthenium hydroxide catalysts [Ru(OH) x /Al 2 O 3 ] by Yamaguchi et al.,4 solid-supported Ru has become an important class of catalyst for nitrile hydration, demonstrating high selectivity for carboxamide formation as well as other practical advantages. 5-8 Although RuCl 3 $nH 2 O itself catalyzes nitrile hydration, the choice of solid support is critically important for achieving sufficient reactivity as well as for retaining Ru species on support. 4,6 Examples of supports successfully used for Ru species include inorganic g-Al 2 O 3 , 4 nanoferrite 5a and magnetic silica, 5b as well as organic chitosan, 5c amberlite 6 and Naon. 7 However, these systems typically require the use of microwave irradiation 5,6 or high reaction temperatures ($175 C). 7 Moreover, the tolerance of basesensitive functional groups such as carboxylic esters has not been documented in these reports. [4][5][6][7] Such chemoselectivity is important in modern organic synthesis, 9 but is generally considered elusive in nitrile hydration promoted by metalloaded heterogeneous catalysts, a single exception (Au/TiO 2 ) 8f notwithstanding. In this work we establish that chitinsupported ruthenium (abbreviated as Ru/chitin) serves as a versatile catalyst for the hydration of nitriles to carboxamides (Scheme 1). Using this system, nitrile hydration can be operated under near-neutral, aqueous conditions without requiring any special apparatus. Moreover, the morphologies of ruthenium nanoparticles on the chitin support were claried by highresolution transmission electron microscopy (HRTEM) analysis.
Aer cellulose, chitin is the second most abundant polysaccharide in nature. 10 It has a wide range of applications in materials, food, medical and environmental contexts. These include in the preparation of chitosan, affinity chromatography, wound-dressing and metal-extraction in water purication. 11 Whereas chitin has been intensively used as a catalyst support for enzymes, 12 its use as a support for metal catalysts has been less widely explored than has that of chitosan. 13,14 So far, chitin has been used as a support for Pt in asymmetric arene hydrogenation, 15 Pd in the hydrogenation of nitrobenzene and unsaturated fatty acid esters 16 and Re in the epoxidation of olens. 14d We expected that chitin would represent a potentially attractive support for the Ru-catalyzed hydration of nitriles because it is highly stable under aqueous conditions and effectively adsorbs Ru species using its carboxamide functionality. 17

Catalytic tests
Ru/chitin catalyst was prepared by impregnating commercially available chitin with an aqueous solution of RuCl 3 $3H 2 O Scheme 1 Hydration of nitriles to carboxamides with Ru/chitin. followed by reduction with NaBH 4 , 18 and was tested for its effectiveness in the hydration of benzonitrile (1a, Table 1). When a mixture of 1a (1.0 mmol), H 2 O (1.0 mL) and Ru/chitin (0.016 mmol Ru, 1.6 mol% Ru) was heated at 120 C for 3 h, the corresponding amide 2a was obtained in 33% 1 H NMR yield (Table 1, entry 1). The presence of ruthenium was found to be essential, with the reaction hardly proceeding without catalyst or using only chitin (entries 2 and 3). Meanwhile, the chitin support was also found to be critical, with RuCl 3 $3H 2 O alone catalyzing the hydration of 1a but with signicantly lower efficiency (entry 4). The optimization of reaction conditions using Ru/chitin increased the yield of 2a from 33% to 87% (entries 5-7). Ru/chitin with a higher Ru content [2.3 mol% Ru, prepared from catalyst precursor (202 mg, 1.2 wt% Ru)] gave slightly better yield still (entry 8). This result proved to be reproducible ( 1 H NMR yields of separate runs: 97%, 91%, 89% and 89%). Analogously prepared Ru catalysts that utilized other polysaccharide supports such as chitosan and cellulose (abbreviated as Ru/chitosan and Ru/cellulose, respectively) were found to be less reactive than Ru/chitin (entries 9 and 10).

Scope and limitation
The scope of the Ru/chitin-catalyzed hydration of nitriles is outlined in Table 2. These reactions were run under comparable conditions to those in entry 8 of Table 1. Benzamide (2a) was obtained in 87% isolated yield (Table 2, entry 1) and variously substituted benzonitriles could be converted to the corresponding amides in good-to-excellent yield (entries 2-13). o-Methyl-substituted 1i was somewhat less reactive (entry 9) though m-and p-substituted analogues reacted in satisfying yields (entries 7 and 8). Benzonitrile 1l, which bore an electronwithdrawing p-nitro group, was completely hydrated in shorter reaction times than 1b, 1c, 1f and 1g, each of which bore electron-donating groups at the para positions. p-Formylbenzonitrile (1k) could be converted to the corresponding amide 2k with an intact formyl moiety in 76% yield, though formation of the hydrate of the aldehyde was also noted under aqueous conditions. Furthermore, heteroaromatic nitriles could be efficiently hydrated to the corresponding amides (entries 14 and 15).
The Ru/chitin system was also applied to the hydration of aliphatic nitriles (Table 2, entries 16-23). Although the hydration reaction proved susceptible to steric hindrance (entry 19), primary and secondary nitriles 1p-r and 1t-w could all be converted to amides (entries 16-18 and 20-23) with retention of olen (entry 21), b-hydroxy (entry 22) and a-methoxy (entry 23) groups in fair-to-good yields.
Importantly, the presence of a base-sensitive carbonyl functionality in methyl ester 1x was tolerated by virtue of the near-neutral conditions that could be used for catalyst preparation 6,18 (Scheme 2). Similarly, an a-amino nitrile conjugated with a redox-sensitive benzyloxycarbonyl (Cbz) group (as in 1y) was converted to protected a-amino amide 2y with retention of the carbamoyl linkage. The tolerance to carboxylic ester and CbzN functionality shown in Scheme 2 illustrates the applicability of the present method to the nitrile hydration of complex molecules bearing redox-or base-sensitive functional groups.

HRTEM analysis
To elucidate the nature of the Ru/chitin catalyst, the catalyst was analyzed by HRTEM. The presence of nanoparticles with a mean size of 2.1 AE 0.4 nm was established . Energy dispersive X-ray spectroscopy (EDX) and measurement of the dspacings (d ¼ 0.23 nm) indicated the presence of both Ru(0) and RuO 2 [ Fig. 1c, inset, and Fig. 1d]. EDX also revealed the presence of Ca and P in both Ru/chitin (Fig. 1d) and chitin ( Fig. 1e and f). This was attributed to calcium phosphate on account of the crustaceous origin of the chitin and was found not to incur signicant catalytic activity (Table 1, entry 3).
TEM analysis of the Ru nanoparticles aer hydration of 1w showed that they remained morphologically essentially unchanged (Fig. 2). In fact, the Ru/chitin catalyst could be reused without signicant loss of catalytic activity (hydration of 1a to 2a, conditions: identical to Table 1, entry 8, rst run, 95% yield; reuse run, 87% yield).

Conclusions
We have established that chitin-supported ruthenium displays high catalytic activity towards the hydration of nitriles to amides under aqueous conditions. The catalyst is easily prepared, and applicable to the hydration of a wide variety of nitriles with aromatic, heteroaromatic and aliphatic substituents. HRTEM analysis of Ru/chitin revealed the presence of ruthenium nanoparticles before and aer hydration reactions, indicating that chitin could serve as an effective solid support for ruthenium nanoparticles.

Experimental section
General comments 1 H and 13 C NMR spectra were recorded on a JEOL ECA-600  Scheme 3 Gram-scale hydration of nitrile 1w. referenced to CF 3 COOH (À78.5 ppm, neat). Infrared (IR) spectra were recorded on a FT-IR6100 (JASCO). High-resolution mass spectrometry (HRMS) was recorded with a Bruker Daltonik micrOTOF-QII spectrometer. Inductively coupled plasmaatomic emission spectroscopy (ICP-AES) spectra were recorded on an Agilent VISTA-PRO. Elemental analyses were recorded on a Yanaco CHN recorder MT-6. These analytical experiments were carried out at the Chemical Instrumental Center, Research Center for Materials Science, Nagoya University. Melting points were recorded on an OptiMelt automated melting point system (Stanford Research Systems). Ruthenium content was analyzed by ICP-AES using yttrium as an internal standard aer digestion of samples (10 mg) in concd HNO 3 (2 mL) at 150 C for 12 h. Products 2a-y were known compounds and their identities were conrmed by comparing with literature data. 6,7,8g,19-34

TEM analysis
High-resolution transmission electron microscopy (HRTEM) analysis was performed on a JEOL JEM-3011 microscope. Samples illustrated in Fig. 1a-d and 2 were prepared as per the typical procedure for the preparation of Ru/chitin (0.016 mmol Ru, vide infra) and by the hydration of 1w (0.5 mmol) using Ru/ chitin (0.016 mmol Ru) at 120 C for 6 h, respectively. Sample preparation required droplet coating of particle dispersions obtained by sonicating in CH 3 CH 2 OH on carbon-coated Cu grids (Agar Scientic, 300 mesh). Electron optical parameters: C S ¼ 0.6 mm, C C ¼ 1.2 mm, electron energy spread ¼ 1.5 eV, beam divergence semi-angle ¼ 1 mrad. Elemental analysis was by energy dispersive X-ray spectroscopy (EDX) using a PGT prism Si/Li detector and an Avalon 2000 analytical system. Spectra were analyzed using the PGT eXcalibur 4.03.00 soware. Observed Cu Ka and Kb emission lines were attributed to scattered electrons impinging on the copper grid. Any minor Fe Ka and Co Ka emission lines of similar intensity were due to parasitic scattering from the lens polepiece. Detailed analysis of particle morphology was performed using Digital Micrograph 3.6.5 by counting the diameters of 100 particles (N), dening intervals of 0. 25

Catalyst preparation
A typical procedure for the preparation of Ru/chitin (0.016 mmol Ru). To a 300 mL round-bottom ask, RuCl 3 $3H 2 O (71.6 mg, 0.30 mmol Ru), H 2 O (50 mL) and chitin (2980.4 mg) were added. The mixture was heated at 50 C for 30 min, and concentrated using a rotary evaporator at 50 C for 25 min (17 mm Hg). The solid was dried at 50 C in vacuo overnight to afford the catalyst precursor (0.8 wt% Ru as determined by ICP-AES analysis, dark green solid, 2784.0 mg). To a 10 mL test tube with a screw cap, a magnetic stirring bar and the catalyst precursor (202 mg, 0.8 wt% Ru), deaerated H 2 O (8 mL) was added under a N 2 atmosphere. Under vigorous stirring, a solution [1.0 mL; a mixture of NaBH 4 (39.4 mg, 1.0 mmol) and deaerated H 2 O (5.2 mL)] was introduced dropwise to the test tube. The mixture was stirred at room temperature (rt) for 3.5 h. The liquid phase was separated by centrifugation (3500 rpm, 5 min) and replaced with H 2 O (8 mL) via syringe. Aer the mixture was stirred at rt overnight, the solid was washed with water (2 times) and dried in vacuo at rt for 2 h to afford Ru/chitin as a grey solid, which was directly used for nitrile hydration.